This is a 371 of PCT/US99 filed Sep. 10, 1999.
The invention relates to a method for using N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (hereinafter referred to as xe2x80x9cduloxetinexe2x80x9d) for the treatment of persistent pain.
For some years, it has been recognized that the chemistry of serotonin and norepinephrine are extremely important in neurological processes, and pharmacologists and medical researchers have been very actively studying the mechanisms of those neurotransmitters in the brain. Concomitantly, the synthesis and study of pharmaceuticals which affect serotonin and norepinephrine processes in the brain are of great interest and are also being intensively studied, both by pharmaceutical chemists and by medical researchers as well.
Duloxetine inhibits the reuptake of both serotonin and norephinephrine, and is being investigated for use as an antidepressant. 3-aryloxy-3-substituted propanamines, such as duloxetine, have been disclosed in U.S. Pat. No. 5,023,269 as being useful for the treatment of pain. This patent, however, does not specify what forms of pain are treated. PCT/US95/13289 discloses that duloxetine is useful for the treatment and prevention of neuropathic pain and migraine. As stated therein, xe2x80x9cNeuropathic pain, as distinct from other varieties of pain, emanates specifically from a neurologic source, as from a nerve which is unnaturally stressed, compressed or otherwise injured, it does not include pain emanating from an injury or inflammation of bone, muscle or other tissue.xe2x80x9d PCT/US95/13289 defines migraine xe2x80x9cas a headache, particularly a very severe headache, which occurs repetitively in patients subject to the condition. It has been treated with partial success with vasoconstrictors but no treatment of migraine in the prior art is reliably successful.xe2x80x9d
For clinical purposes, pain may be divided into two categories: acute pain and persistent pain. Acute pain is provoked by noxious stimulation produced by injury and/or disease of skin, deep somatic structures or viscera, or abnormal function of muscle or viscera that does not produce actual tissue damage. On the other hand, persistent pain can be defined as pain that persists beyond the usual course of an acute disease or a reasonable time for an injury to heal or that is associated with a chronic pathologic process that causes continuous pain or the pain recurs at intervals for months or years. If pain is still present after a cure should have been achieved, it is considered persistent pain. For the purpose of the present invention, persistent pain can be chronic non-remitting or recurrent. The difference in definition between acute and persistent pain is not merely semantic but has an important clinical relevance. For example, a simple fracture of the wrist usually remains painful for a week to 10 days. If the pain is still present beyond the typical course of treatment, it is likely that the patient is developing reflex sympathetic dystrophy, a persistent pain syndrome that requires immediate effective therapy. Early and effective intervention potentially prevents the undue disability and suffering, and avoids the potential development of a condition that becomes refractory to therapy.
Acute and chronic pain differ in etiology, mechanisms, pathophysiology, symptomatology, diagnosis, therapy, and physiological responses. In contrast to the transitory nature of acute pain, persistent pain is caused by chronic pathologic processes in somatic structures or viscera, by prolonged and sometimes permanent dysfunction of the peripheral or central nervous system, or both. Also, persistent pain can sometimes be attributed to psychologic mechanisms and/or environmental factors.
Persistent pain is a disease state that is one of the most important health problems in industrialized nations throughout the world. Persistent pain and suffering, regardless of cause, has serious physical, behavioral, mental, psychologic, social, and economic effects on both the patient and the family, and is very costly to society.
The mental effects of prolonged or persistent pain are greatly influenced by the duration, intensity, and periodicity of the persistent pain, by the personality and psychologic makeup of the individual, and by various socioloaic and economic factors. The duration of the persistent pain is an important factor in determining the mental effects; for while the average individual can briefly bear, both psychologically and physiologically, even the most severe pain, if such pain is prolonged it exerts effects which cause mental and physical deterioration. Prolonged, persistent, and intense pain interferes with thought processes and dominates the entire organism.
The impact of persistent pain on society is equally devastating as its effects on the sufferer. Patients develop problems with their families and friends, and, as previously mentioned, decrease their social interactions. Household chores (cooking, caring for a sick child, etc.), social and familial obligations are frequently cancelled. Some patients are unable to work, some are ineffective at work, others are encouraged not to work, and still others lose their jobs because of frequent absences. In fact, the unemployment rate of some chronic pain conditions can be 4-5 times higher than the average unemployment rate in the United States. These profound societal effects may render the patient an economic liability rather than an asset.
Current therapies for persistent pain include opiates, barbiturate-like drugs such as thiopental sodium and surgical procedures such as neurectomy, rhizotomy, cordotomy, and cordectomy. These therapies have significant drawbacks. Opiates and barbiturate-like drugs have limiting side effects and are addictive. Tricyclic antidepressants and anticonvulsants are marginally effective, and also are associated with some limiting side effects. Electrical stimulation, e.g., TENS has limited success in chronic pain. Surgical procedures are expensive, irreversible and often fail to provide long-term relief from persistent pain. Faced with suboptimal therapy for persistent pain, the patient suffers more, complains more, and becomes more desperate and dissatisfied with their healthcare. As a consequence, the patient seeks and consumes more direct and indirect healthcare resources.
In light of these realities, there is a demand for more effective analgesic agents, targeted specifically for persistent pain, which have a superior safety and tolerability profile and are non-addictive. The ideal analgesic would reduce the awareness of pain, produce analgesia over a wide range of pain types, act satisfactorily whether given orally or parenterally, produce minimal or no side effects, and be free from a tendency to produce tolerance and drug dependence.
The present invention addresses the need for a safe and effective treatment of persistent pain by providing a method of treating persistent pain.
In accordance with the present invention, there is provided a method of treating persistent pain comprising the administration to a patient in need of such treatment of an effective amount of duloxetine.
The present invention also provides the use of duloxetine for the manufacture of a medicament for treating persistent pain.
Furthermore, the present invention provides the use of duloxetine for treating persistent pain.
The term xe2x80x9ctreatingxe2x80x9d for purposes of the present invention, includes prophylaxis or prevention, amelioration or elimination of a named condition once the condition has been established.
The term xe2x80x9cpatientxe2x80x9d for purposes of the present invention is defined as any warm blooded animal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
For purposes of the present invention, the term xe2x80x9cacute painxe2x80x9d is defined as pain which is provoked by noxious stimulation produced by injury and/or disease of skin, deep somatic structures or viscera, or abnormal function of muscle or viscera that does not produce actual tissue damage.
The term xe2x80x9cpersistent painxe2x80x9d as used herein, is defined as pain that persists beyond the usual course of an acute disease or a reasonable time for an injury to heal or that is associated with a chronic pathologic process that causes continuous pain or the pain recurs at intervals for months or years. If pain is still present after a cure should have been achieved or beyond a typical course of treatment, it is considered persistent pain. The length of time that must pass before pain is persistent depends upon the nature of the pain and the typical course of treatment associated with the pain. Pain is persistent if it lasts beyond a typical course of treatment.
Persistent pain includes, but is not limited to, tension-type headache, musculoskeletal pain, pain associated with somatoform disorders, visceral pain, painful diabetic neuropathy, vascular pain, arthritic pain, back pain, neck pain, shoulder pain, cancer pain, pain associated with AIDS, postoperative pain, and post-burn pain.
Duloxetine is effective in treating persistent pain as defined above. Also, duloxetine is useful in treating other conditions where there is hyper-sensitization to painful signals, hyperalgesia, allodynia, enhanced pain perception, and enhanced memory of pain. Duloxetine will improve coping with pain.
Tension-type headache is the most common form of primary or idiopathic headaches, i.e. those that are not related to an identifiable cause. Two types of tension-type headaches are recognized; episodic tension-type and chronic tension-type. xe2x80x9cChronic tension-type headachexe2x80x9d as used herein, is defined by International Headache Society criteria (Cephalalgia 1988;8 (Suppl 7): 1-96) as recurrent headaches that are xe2x80x9cpresent for at least 15 days a month during at least 6 months. The headache is usually pressing/tightening in quality, mild or moderate in severity, bilateral and does not worsen with physical activity. Nausea, photophobia or phonophobia may occur.xe2x80x9d
Chronic tension-type headache (TTH) occurs in 2-3% of the population. The severity of the pain of TTH, unlike that of episodic TTH, is usually moderate to severe. Chronic TTH is differentiated from migraine clinically based on the following features: bilaterality of pain; non-pulsating quality; often varying locations of pain; seldom association with both light (photophobia) and noise (phonophobia) sensitivity. In addition, smell sensitivity (osmophobia) is not a symptom of TTH; absence of neurological accompaniments such as visual or sensory auras.
xe2x80x9cSomatoform disorders,xe2x80x9d as used in the present invention, are defined as having, as a common feature, the presence of physical symptoms that suggest a general medical condition which are not fully explained by a general medical condition, by the direct effects of a substance, or by another mental disorder. (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, p. 445). Somatoform disorders include functional somatic syndromes, including those referenced in Barsky A J, Borusn J F. Functional Somatic Syndromes. Ann Intern Med 1999;130:910-921, such as, but not limited to, multiple chemical sensitivity, sick building syndrome, repetition stress injury, chronic whiplash, chronic lime disease, side effects of silicon breast implants, candidiasis hypersensitivity, the Gulf War Syndrome, food allergies, mitral valve prolapse, and hypoglycemia.
The term xe2x80x9cmusculoskeletal painxe2x80x9d as used herein, includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndrome.
The term xe2x80x9cmyofascial painxe2x80x9d as used herein, includes, but is not limited to, temporo-mandibular joint disease (TMJ) and fibromyalgia with or without chronic fatigue syndrome. The term xe2x80x9cfibromyalgiaxe2x80x9d, for purposes of the present invention, includes, but is not limited to, that pain which is defined by the American College of Rheumatology (ACR) classification (Wolf F, et al., The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum 33:160-172;1990.) Fibromyalgia is a clinical syndrome characterized by chronic muscle aches, stiffness, fatigue, non-restorative sleep, and localized tender points. The ACR criteria for fibromyalgia are: 1) widespead aching in all four quadrants and in the axial skeleton for more than least 3 months in duration; and 2) pain in 11 or more of 18 tender points under digital pressure examination.
For the purposes of the present invention, xe2x80x9cpainful diabetic neuropathyxe2x80x9d is pain which is secondary to injury to nerves as a complication of diabetes mellitus. Injury to nerves in diabetes mellitus is caused, at least in part, by decreased blood flow and high blood-sugar levels. Some diabetics will not develop neuropathy, while others may develop this condition relatively early. Diabetic neuropathies may be classified into mononeuropathies involving one or more focal sites and generalized polyneuropathies which may be diffuse, symmetric and often predominantly involving sensory modalities [Merrit""s Textbook of Neurology, 9th ed., ed by L. P. Rowland, Williams and Wilkins, 1995, p. 669]. Manifestations of diabetic neuropathy can include dysfunction of autonomic nerves resulting in dysregulation of vital functions including the heart, smooth muscles, and glands. Low blood pressure, diarrhea, constipation, and sexual impotence also result from autonomic neuropathies. Cranial neuropathies may affect vision. Sensory neuropathies affect the nerves that carry sensory information from the skin and other sense organs to the brain. Loss of sensation of touch, pressure, vibration and temperature to a body part or area may result from sensory neuropathies. Diabetic neuropathies are sometimes, but not always, accompanied by pain. Painful diabetic neuropathy tends to develop in stages. Early on, intermittent pain and tingling may be noted in the extremities of nerve terminal fields, particularly the feet in the case of autonomic or sensory neuropathy, or in the face and around the eye in the case of cranial neuropathy. In later stages, the pain is more intense and constant. Finally, a painless neuropathy develops when pain sensation is lost to an area, which greatly increases the risk of severe tissue injury without pain as an indicator of injury.xe2x80x9d
The term xe2x80x9cvisceral painxe2x80x9d includes, but is not limited to that pain associated with irritable bowel syndrome (IBS) with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis.
The term xe2x80x9cvascular painxe2x80x9d, for purposes of the present invention, is that pain xe2x80x9cproduced by one or more of the following pathophysiologic factors: (a) inadequate perfusion of tissues with consequent transient or continuous ischemia such as occurs in the muscles of the limb during exercise, ischemia of the skin that produces rest pain, and ischemia of a viscus such as the heart or gastrointestinal tract; (b) secondary changes such as ulcerations or gangrene in the skin or abdominal viscera; (c) sudden or accelerated changes in the vascular dimension of large vessels such as occurs with aneurysm; (d) rupture of the aorta with consequent spillage of blood that stimulates nociceptive fibers in the parietal peritoneum or parietal pleura; (e) intense spasm consequent to the intra-arterial injection of severe irritant on the endothelium of the artery; and (f) impairment of venous return with consequent massive edema that rapidly stretches fascial compartmentsxe2x80x9d. (J. J. Bonica et al., The Management of Pain Vol. 1 (2nd ed., Philadelphia: Lea and Febiger, 1990.) Examples include, but are not limited to, arteriosclerosis obliterans, thromboangitis obliterans, acute arterial occlusion, embolism, congenital arteriovenous aneurysm, vasospastic disease, Raynaud""s disease, acrocyanosis, acute venous occlusion, thrombophlebitis, varicose veins, and lymphedema.
The term xe2x80x9carthritic painxe2x80x9d includes, but is not limited to, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthritis, gout, pseudogout, infectious arthritis, tendonitis, bursitis, bone lesions and joint soft tissue inflammation.
For purposes of the present invention, xe2x80x9cnociceptive painxe2x80x9d is pain caused by a tissue-damaging process that excites nociceptive afferents or pain which is provoked by prolonged excitation of nociceptors. Persistent pain which arises from nociceptive pain may be due to persistent noxious stimulation of nociceptors or their sensitizations or both, or they may be initiated by these factors and prolonged by their persistence, by various reflex mechanisms and by other factors.
The term xe2x80x9cnociceptionxe2x80x9d as used herein refers to the neural mechanisms by which noxious stimuli are detected. Nociception involves two steps: transductions of noxious stimuli by peripheral nerve endings and transmission of these signals to the central nervous system.
The present invention is useful for the treatment of nociceptive pain or pain that arises from a combination of nociceptive and neuropathic etiologies. It is preferred that the pain to be treated is nociceptive pain.
It is also believed by those of ordinary skill in the art that central sensitization contributes to the expression of persistent pain. The term xe2x80x9ccentral sensitizationxe2x80x9d as used herein is defined as hyperexcitability of spinal neurons.
Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which shows its high potency in the inhibition of serotonin and norepinephrine uptake. The term xe2x80x9cduloxetinexe2x80x9d as used herein, refers to any acid addition salt or the free base of the molecule.
Duloxetine is a safe drug, and its use in the treatment of persistent pain is a superior treatment because of its improved safety. The compound is particularly selective, having few if any physiological effects besides those on norepinephrine and serotonin processing, and therefore is free of side effects and unwanted activities, unlike the limiting side effects of other similar drugs used for the treatment of persistent pain. Further, it is effective at relatively low doses, as discussed below, and may safely and effectively be administered once per day. Thus, difficulties created by the multiple dosing of patients are completely avoided.
The effective amount or dose of duloxetine for treating persistent pain is in the range from about 1 mg/day to about 200 mg/day. The preferred adult dose is in the range from about 40 to about 150 mg/day, and a more highly preferred adult dose is from about 60 to about 120 mg/day. The optimum dose for each patient, as always, must be set by the physician in charge of the case, taking into account the patient""s size, other medications which the patient requires, severity of the persistent pain and all of the other circumstances of the patient.
Since duloxetine is readily orally absorbed and requires only once/day administration, there is little or no reason to administer it in any other way than orally. It is produced in the form of a clean, stable crystal, and thus is easily formulated in the usual oral pharmaceutical forms, such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable. It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as, but not limited to, injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer duloxetine as a tablet or capsule and such pharmaceutical forms are recommended.
A preferred duloxetine enteric formulation as disclosed in U.S. Pat. No. 5,508,074, which is hereby incorporated by reference, is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer. The following example demonstrates the preparation of a preferred such formulation.